As diseases associated with the activity of vanilloid receptor (Nagy et al., 2004, Eur. J. Pharmacol. 500, 351-369) pain such as acute pain, chronic pain, neuropathic pain, post-operative pain, rheumatic arthrodynia, osteoarthritis pain, postherpetic neuralgia, neuralgia, headache, and migraine (Petersen et al., 2000, Pain, 88, pp 125-133; Walker et al., 2003, J. Pharmacol. Exp. Ther., 304, pp 56-62); nerve-related diseases such as neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, and stroke (Park et al., 1999, Arch. Pharm. Res. 22, pp 432-434; Kim et al., 2005, J. Neurosci. 25(3), pp 662-671); diabetic neuropathy (Kamei et al., 2001, Eur. J. Pharmacol. 422, pp 83-86); fecal urgency; irritable bowel syndrome (Chan et al., 2003, Lancet, 361, pp 385-391); inflammatory bowel disease (Yiangou et al., 2001, Lancet, 357, pp 1338-1339); disease of digestive organ such as stomach-duodenal ulcer and Crohn's disease (Holzer P, 2004, Eur. J. Pharm. 500, pp 231-241; Geppetti et al., 2004, Br. J. Pharmacol., 141, pp 1313-1320); disease of respiratory organ such as asthma, chronic obstructive pulmonary disease (Hwang et al., 2002, Curr Opin Pharm pp 235-242; Spina et al., 2002, Curr Opin Pharm pp 264-272); urinary incontinence (Birder et al., 2002, Nat. Neuroscience, 5, pp 856-860); urinary bladder hypersensitiveness (Birder et al., 2001, Proc. Natl. Acad. Sci. 98, pp 13396-13401); neurotic/allergic/inflammatory skin disease such as psoriasis, pruritus and prurigo (Southall et al., 2003, J. Pharmacol. Exp. Ther., 304, pp 217-222); irritation of skin, eye or mucous membrane (Tominaga et al., 1998, Neuron 21 pp 531-543); hyperacusis; tinnitus; vestibular hypersensitiveness (Balaban et al., 2003, Hear Res. 175, pp 165-70); cardiac disease such as inotropic ischemia etc. (Scotland et al., 2004, Circ. Res. 95, pp 1027-1034; Pan et al., 2004, Circulation, 110, pp 1826-1831) can be enumerated.
The vanilloid receptor (VR1) is the receptor for capsaicin (8-methyl-N-vanillyl-6-nonenamide), a pungent ingredient in hot peppers. The molecular cloning thereof was also reported in 1997 (Caterina et al., 1997, Nature 389, pp 816-824). This receptor is a non-selective cation channel composed of 6 transmembrane domains and belongs to the TRP channel family. Recently, it was named TRPV1. On the other hand, it is known that the vanilloid receptor is activated by stimuli such as capsaicin, resiniferatoxin, heat, acids, anandamide, lipid metabolites or the like; thus it plays a crucial role as a molecular integrator of physico-chemically noxious stimuli in mammals (Tominaga et al., 1998, Neuron 21 pp 531-543; Hwang et al., 2000, PNAS, 97, pp 6155-6160). Activation of the vanilloid receptor by endogenous/exogenous stimuli leads to not only transmission of noxious stimuli, but also liberation of neuropeptides such as substance P, CGRP (Calcitonin Gene-Related Peptide) and the like, thereby causing neurogenic inflammation. The vanilloid receptor is highly expressed in primary afferent sensory neurons. It is also reportedly expressed in various organs and tissues such as the bladder, kidney, lungs, intestines and skin, and in the central nervous system (CNS) including the brain and non-neuronal tissues (Mezey et al., 2000, PNAS, 97, pp 3655-3660; Stander et al., 2004, Exp. Dermatol. 13, pp 129-139; Cortright et al., 2001, BBRC, 281, pp 1183-1189). In particular, TRPV1 receptor knock-out mice exhibit a normal response to harmful physical stimuli, but show a reduction in pain responses and sensory sensitivity to thermal stimuli by vanilloid, and exhibit little hyperalgesia to thermal stimuli even in an inflammatory state (Caterina et al., 2000, Science 288, pp 306-313; Davis et al., 2000, Nature 405, pp 183-187; Karai et al., 2004, J. Clin. Invest., 113, pp 1344-1352). Lately, an additional role of the vanilloid receptor is also anticipated by presentation of possibility that the vanilloid receptor may be present in the form of a heteromultimer with TRPV3, another TRP channel (Smith et al., 2002, Nature, 418, pp 186-190).
As mentioned above, the vanilloid receptor knock-out mice exhibited reduced responses to thermal or noxious stimuli, thus raising the possibility that vanilloid receptor antagonists may be utilized for prevention or treatment of various pain conditions. Recently, this possibility is supported by the report that the well-known vanilloid receptor antagonist, capsazepine also decreases hyperalgesia caused by physical stimuli in models of inflammatory and neuropathic pain (Walker et al., 2003, JPET, 304, pp 56-62; Garcia-Martinez et al., 2002, Proc. Natl. Acad. Sci. 99, 2374-2379). In addition, treatment of the primary culture of afferent nerve cells with the vanilloid receptor agonist, capsaicin etc., results in damage to nerve functions and furthermore death of nerve cells. The vanilloid receptor antagonist exerts defense actions against such damage to nerve functions and nerve cell death (Holzer P, 1991, Pharmacological Reviews, 43, pp 143-201; Mezey et al., 2000, PNAS, 97, 3655-3660). The vanilloid receptor is expressed in all regions of the gastrointestinal tract, for example, ganglia of tensor, tunica muscularis, mucosa and epithelial cells. In particular, the vanilloid receptor is highly expressed in inflammatory disorders of the colon and ileum.
In addition, activation of the vanilloid receptor stimulates sensory nerves, which in turn causes release of neuropeptides which are known to play a critical role in pathogenesis of bowel disorders. The role of the vanilloid receptor in development of gastrointestinal disorders is well elucidated and documented in recent scientific papers and journals, for example, Holzer P, 2004, Eur. J. Pharm. 500, pp 231-241; Geppetti et al., 2004, Br. J. Pharmacol., 141, pp 1313-1320. According to such references, it seems that the vanilloid receptor antagonists will be effective for prevention or treatment of gastrointestinal diseases such as gastro-esophageal reflux disease (GERD) and gastroduodenal ulcer (DU). It has been reported that the number of sensory nerves expressing the vanilloid receptor is increased in patients suffering from irritable bowel syndromes and such increased expression of the vanilloid receptor is known to be involved in the development of the disease (Chan et al., 2003, Lancet, 361, pp 385-391). Other investigations showed that expression of the vanilloid receptor is significantly increased in patients suffering from inflammatory bowel disorders. Taken together, it appears that the vanilloid receptor antagonist may also be therapeutically effective for such bowel disorders (Yiangou et al., 2001, Lancet, 357, pp 1338-1339). The vanilloid receptor-expressing afferent nerves are abundantly distributed in airway mucosa. Bronchial hypersensitivity is very similar to hyperalgesia, and protons and lipoxygenase products, known as endogenous ligands for the vanilloid receptor, are well known as crucial factors responsible for development of asthma and chronic obstructive pulmonary diseases (Hwang et al., 2002, Curr. Opin. Pharm. pp 235-242; Spina et al., 2002, Curr. Opin. Pharm. pp 264-272). Further, it has been reported that air-polluting substances, which are a kind of asthma-causing substances, i.e., particulate matter specifically acts on the vanilloid receptor and such action is inhibited by capsazepine, thus suggesting the possible applicability of vanilloid receptor antagonists to respiratory diseases (Veronesi et al., 2001, NeuroToxicology, 22, pp 795-810). Urinary bladder hypersensitiveness and urinary incontinence are caused by various central/peripheral nerve disorders or injury, and capsaicin-responsive sensory nerves play an important role in bladder function control and inflammation. In addition, immunoreactivity of the vanilloid receptor was reported in urinary bladder epithelium (urothelium) in rats and it was found that bladder overactivity induced by capsaicin was due to stimulation of vanilloid receptors present in nerve fibers, or various transmitters which are released by vanilloid receptors (Birder et al., 2001, Proc. Natl. Acad. Sci. 98, pp 13396-13401). Further, VR1 (TRPV1)−/− mice are anatomically normal, but exhibit non-excretory bladder contractions by low contractile force, as compared to normal mice, thus indicating that the vanilloid receptor affects functions of the bladder (Birder et al., 2002, Nat. Neuroscience, 5, pp 856-860). Some of vanilloid agonists are recently under development as therapeutics for treating bladder diseases. Vanilloid receptors are distributed in human epidermal keratinocytes as well as in primary afferent sensory nerves (Denda et al., 2001, Biochem. Biophys. Res. Commun., 285, pp 1250-1252; Inoue et al., 2002, Biochem. Biophys. Res. Commun., 291, pp 124-129), and are then involved in transmission of various noxious stimuli and pains such as skin irritation and pruritus, thereby having close correlation with etiology of dermatological diseases and disorders such as skin inflammation, due to neurogenic/non-neurogenic factors. This is supported by the report that the vanilloid receptor antagonist, capsazepine inhibits inflammatory factors in human skin cells (Southall et al., 2003, J. Pharmacol. Exp. Ther., 304, pp 217-222).
Based on the above-mentioned information, development of various vanilloid receptor antagonists is under way, and some patents and patent applications relating to vanilloid receptor antagonists under development were recently published, in which the above mentioned information is described well (Rami et al., 2004, Drug Discovery Today: Therapeutic Strategies, 1, pp 97-104).
As a result of extensive and intensive studies based on the theoretical background discussed above, the present inventors have synthesized novel compounds having antagonistic activity by selective action on a vanilloid receptor and thus completed the present invention. Surprisingly, it has been identified that compounds having a dibenzyl urea, dibenzylamide or dibenzylcinnamoyl structure and carrying a C2-C5 alkenyl or C2-C5 alkynyl as well as an amine-containing substituent on one of their phenyl ring are particularly active modulators of the vanilloid receptor.
Therefore, it is an object of the present invention to provide novel compounds useful as a potent antagonist for a vanilloid receptor, isomer thereof and pharmaceutically acceptable salts thereof; and a pharmaceutical composition comprising the same.